The ?-thalassemias and hemoglobinopathies are serious genetic blood diseases, which are WHO-designated as a growing global health burden. The disorders decrease production or alter the structure of the ?-chain of adult hemoglobin A, and cause hemolytic anemia, chronic organ damage, and early mortality. Fetal globin (HbF) is another type of normal hemoglobin, which is expressed during fetal development but suppressed in infancy. Decades of research have shown that any incremental increase in HbF reduces the severity of sickle cell disease and ?- thalassemia. Pharmacologic augmentation of fetal hemoglobin (?-globin chain) production, is accepted as one therapeutic modality to reduce the underlying pathology. We applied high- throughput screening to study a library of drugs currently approved by the EMA or FDA for other medical conditions, identified a small panel of previously unrecognized drugs which induce the fetal globin gene, and validated their action in patients? red blood cell progenitors, nonhuman primates, and transgenic mice. One therapeutic, Benserazide, induced fetal globin up to 30-fold over baseline with intermittent oral treatment in anemic baboons, and was found to abolish, suppress, or displace 4 potent molecular repressors of the fetal gene promoter, BCL11A, LSD-1, KLF-1, and HDAC3, causing ?chemical gene editing?. Benserazide has been used for 4 decades in Europe and Canada as an amino acid decarboxylase inhibitor, to enhance the PK of another active agent in a combination tablet for treatment of Parkinson?s disease, has a benign safety profile and is considered safe at chronic doses up to 1300 mg per day. This proposal will evaluate Benserazide at human equivalent doses extrapolated from active dosing in anemic baboons and transgenic mice, for tolerability, pharmacokinetics, and fetal globin expression assays in up to 24 patients with beta thalassemia intermedia and up to 12 patients with sickle cell disease. The Aims include: Aim I: To evaluate tolerability and PK of 3 doses of Benserazide in 24 beta thalassemia intermedia (BTI) patients, in 3 dose-escalating cohorts and an expansion cohort treated for 12 weeks Aim II: To investigate preliminary activity of Benserazide in inducing HbF expression in up to 16 BTI patients, and in one cohort of patients with sickle cell disease, as change from baseline in: IIa. F-reticulocytes, F-cells, MFI, HbF, total hemoglobin and hematocrit IIb. Assays of markers of hemolysis (STfr, LDH, bilirubin) The study should provide a basis for conducting definitive Ph2 or 3 clinical trials of a molecularly targeted therapy for these two global blood disorders.